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The prequalification project l.jpg

The prequalification project

The prequalification project started in 2001 to assure medicinal products supplied for procurement meet WHO norms and standards (quality, safety, efficacy) (http://mednet3.who.int/prequal/)Requirements for prequalification:1. Quality part of dossier acceptable2. Safety/efficacy part of dossier acceptable3. Manufacturing site (FPP, API) compliant with WHO norms and standards for GMP4. Study compliant with norms and standards for GCP (WHO) and GLP (GPNPCL, and OECD as appropriate)


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WHO Glossary

Contract Research organization (CRO)

A scientific organization (commercial, academic or other) to which a sponsor may transfer some of its tasks and obligations. Any such transfer should be defined in writing.

Good Clinical Practice (GCP)

A standard for clinical studies which encompasses the design, conduct, monitoring, termination, audit, analyses, reporting and documentation of the studies and which ensures that the studies are scientifically and ethically sound and that the clinical properties of the pharmaceutical product (diagnostic, therapeutic or prophylactic) under investigation are properly documented.

Good Laboratory Practice (GLP)*

A quality system concerned with the organisational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported (OECD)

*as applied to human bioanalysis studies


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Bioequivalence studies

Products to be prequalified usually multisource (generic) products

Therapeutic equivalence generally demonstrated by bioequivalence study in CROs

Findings of deficient and discrepant bioequivalence data and non-compliance with norms and standards for GCP (WHO) and GLP (WHO GPNPCL, and OECD as appropriate)


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Reference documents...

Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. WHO Technical Report Series, No. 850, Annex 3, 1995.

Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. WHO Technical Report Series, No. 863, 1996.

OECD Principles of good laboratory practice (GLP). [C(97)186/Final], 1997.

Good practices for national pharmaceutical control laboratories. WHO Technical Report Series, No. 902, Annex 3, 2002


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CRO inspections

CRO inspections performed by WHO May-Nov 2004

Study-specific

Team of 3 inspectors

6 CROs in India (all for HIV/AIDS products)


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CRO inspections- areas covered

Clinical

General organization, the protocol, protection of trial subjects, responsibilities of the investigator, responsibilities of the sponsor/monitor, record-keeping and handling of data, handling and accountability for pharmaceutical products, quality assurance for the conduct of a clinical trial

Bioanalytical

Apparatuses/materials/reagents, SOPs, performance of the study, test and reference products, storage and retention of records and materials, quality assurance

PK analysis and statistics

Reporting



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Clinical General organization

Transfer of responsibilities from sponsor to CRO not documented

Unclear procedure for assigning Subject ID (two subjects assigned the same ID on the Attendance Sheet Form!)

No SOP for drug dispensing

No SOP for assigning study numbers

No site staff sample signature log for the study

Organization chart not readily available, no version date

No QC system to ensure accuracy and consistency in recording and document control


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ClinicalThe protocolWHO GCP 1 & Appendix 2

Validity of screening tests?

No CRFs designed for the study (raw data not transferred to CRFs)

In some cases, several CRFs missing – only a few still available as archived

Not included:

Name and address of sponsor

Description of trial site and information on investigators

Method and procedure of randomisation, randomisation schedule and how it was established

Method and timing of subject allocation to investigational groups


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ClinicalThe protocol, cont'd

Not included:

Information to volunteers

Procedures for maintaining subject identification code list

Statistical justification for the number of subjects

Method for measuring blood pressure - sitting or supine? And if both, which value to use…

Type of test tubes for blood sampling

PK analysis; Method of calculating PK pararmeters, e.g. AUC, how to deal with deviations from planned sampling times

How to evaluate the results, including statistics and how to handle withdrawals


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ClinicalProtection of trial subjectsWHO GCP 3

Independence of EC questionable

Chairman had expanded his own authorisation (Chairman's approval invalid)

Unclear whether study protocol, ICF and related documentation had been properly discussed at the EC meeting

Unclear if one or two ICFs

Unclear when EC convened

Discrepancy between EC approval form and the minutes of the corresponding meeting (who present/who absent)

Some relevant EC documents (register page) could not be produced


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ClinicalProtection of trial subjects, cont'd

Screening before EC approval

No written consent before screening (e.g. lab tests)

Freely given informed consent/valid written consent?

One subject signed ICF with thumb print…

ICF seriously lacking in information

Professional terminology (Stevens-Johnsons syndrome, thrombocytopenia etc)

Identification system (finger print matching) to ensure volunteers had not participated in another study within the last 3 months not validated

No measures to protect confidentiality of subjects


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ClinicalResponsibilities of the InvestigatorWHO GCP 4

No protocol deviations according to the study report!

However a number of deviations:

Source of reference product unclear (US, UK or India?)

Amount of meal/time for consumption only recorded for some subjects

Deviations in some of the meal times (not mentioned in the study report)

No anticoagulant in tubes contrary to protocol (or different anticoagulant)

ESR and plasma cholesterol required but not done

Na, K, Cl, bleeding time and ECG not required, however tests were done


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ClinicalResponsibilities of the Investigator, cont'd

Deviations, cont'd;

Protocol and ICF were supposed to be reviewed by EC but ICF appears not to have been

Vital signs recorded at absolute rather than relative timepoints contrary to protocol

Blood sample drawn at times contrary to protocol – deviations not mentioned in the study report

Incomplete recording of vital signs

One subject's identity not verified

Date of birth of subjects?

Violations of incl/excl criteria

No maintenance, calibration or log book for X-ray machine

Investigator CV not signed or dated – CV current?


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ClinicalResponsibilities of the Sponsor/MonitorWHO GCP 5 & 6

No monitors appointed by the sponsor. No monitoring/audit reports available.

No evidence of assessment of the trial site (labs, equipment, staff, facilities)

Audits performed by the sponsor, but scheduled after the report was issued and no audits reports available

Issues with certificate of insurance subscribed by the CRO


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ClinicalRecord-keeping and handling of dataWHO GCP 8

No study or protocol number on ECGs to link them to the study.

Of 95 ECGs copied by inspectors, 43 appeared to have been recorded from one subject, 21 from a second subject and 11 from a third subject

For several subjects the "screening" and "follow up" ECGs appeared to have been recorded from different subjects

No mention on ECG print outs of the identity of the equipment used

Some ECGs had no date of birth of subject

Doubts as to the authenticity of ECG documentation!


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ClinicalRecord-keeping and handling of data, cont'd

No mention of name, batch no or expiry date of the in vitro diagnostic serology test kit in source doc's or lab data

Discrepancies between Attendance Sheet Forms and CRF Screening pages (screening visit dates)

Discrepancies between Volunteer Card and CRF (smoking/alcohol)

Unclear dosing time

Identical (actual) blood sampling times for two subjects!

Recordings of actual sampling times - same handwriting, however initials of phlebotomists different at different sampling times!

Deviations from planned blood sampling times not reported

Inconsistencies in screening dates


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ClinicalRecord-keeping and handling of data, cont'd

Deliberate attempt to change subject code

Discrepancies between source documents and study report

Method/procedure of randomization not documented

No record of subjects screened

Source documents not kept

Original entry erased!

Type of tubes and anticoagulant used not documented

CRF used was not specific to the study

Errors on the CRFs

Lab ref ranges on CRF different from those reported by the lab

Expiry date of medications not recorded on CRFs

Appearance of tablets incorrectly described

Missing: Lab data, ECG…

Final study report not signed by the monitor


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ClinicalHandling and accountability for pharmaceutical productsWHO GCP 10

What was given?

How much was given?

Treatment sequence? Cross-over?

Labelling?

Dispensing or dosing? Confusion between the two!

Dispensing not documented. SOP? Dispensing dates?

Drug unused?

Drug destroyed?

Storage?


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ClinicalQuality Assurance for the conduct of a clinical trialWHO GCP 1 & 2

QA system in place at all (see above)?

No records of labels printed

No record of reconciliation procedure

No SOP for labelling/dispensing of empty vials and return of filled vials

No SOP for further sample handling (centrifugation etc)

No SOP for blood sampling

No SOP for sample transport

No SOP in the event of freezer break down

No SOP for handling of out-of-specification results

No record/minutes of a pre-study meeting

SOPs from before 2001 not archived or available during the inspection


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BioanalyticalApparatuses/Material/ReagentsOECD GLP 4

Pipettes not identified – no traceability

Infrequent or no controls of balance (calibrated weights?)

Storage temperature?

No validation of time of freezer temp recording

Record of freezer contents?

Centrifuge maintenance?

Expiry date for Vacutainers?

Calculation of concentrations


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BioanalyticalSOPsOECD GLP 1 & 7

Type of C18 cartridges used (solid phase extraction) not described in the method SOP and not reported in the study report

Only one SOP ("Calculation and reporting of bioanalytical data") for the bioanalytical part of BE trials

SOPs from before 2001 not archived or available during the inspection (most of the ones for the study in question)


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BioanalyticalPerformance of the studyOECD GLP 8

Matrix effects?

Acceptance criteria for analytical runs not in accordance with study plan

Chromatograms without unique study number

Bioanalytical method used =method described in the study report?

No or improper source documents

Errors in documentation re preparation of stock solutions, calibration and control samples

Discrepancies between volumes prepared and volumes actually used

Origin of blank plasma?


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BioanalyticalPerformance of the study, cont'd

Identical chromatograms with different identities

Integration reports of identical chromatograms showed different peak areas, even though peak integration parameters were identical

Identical chromatograms had different peak areas but the same area percent

Inconsistencies noted between visual appearances of peaks and the area in the integration reports

Long term stability of plasma samples?

Authenticity of chromatograms and peak areas?


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BioanalyticalPerformance of the study, cont'd

Interferences at retention time of lamivudine – concentrations still used and reported

Discrepancies between concentrations printed on chromatograms and reported, and those recalculated by the inspectors from the calibration curve parameters

– method failed validation acceptance criteria


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BioanalyticalTest and reference substancesOECD GLP 5 & 6

Batch numbers of reference substances used not documented – were the batches used, those for which CoAs were available?

Not possible to verify purity of reference substances!


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BioanalyticalStorage and retention of records and materialsOECD GLP 10

Only uncertified copies of chromatograms at the CRO (original chromatograms reportedly sent to sponsor)

Documents relating to chromatographic analysis of samples not available during the inspection.


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BioanalyticalQuality assurance OECD GLP 1 & 2

The number and critical nature of the deviations from OECD GLP (below) highlight the lack of or insufficiency of the Quality Assurance system implemented by the CRO


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PK and statistical analysisWHO GCP 9

Method of calculating AUC not specified in the study report

AUC stated as calculated up to 8 hs when in fact it was up to last conc, 24 hs

PK and statistical calculations


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ReportingOECD GLP 2 & 9

Same or different stock solution for calibration/control samples?

Concentrations <LOQ or LOD reported – SOP not followed

Some zidovudine conc's were lamivudine conc's

Discrepancy between conc on chromatogram and in study report

Composition of buffer for sample preparation not in SOP

Not specified in study protocol/report which results to use

Errors in the bioanalytical report

Rounding errors


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